Recently, Shi and Wang’s research group have developed a biomimetic design reagent DMTT for the selective d3-methylation of complex molecules bearing several possible reactive sites with excellent selectivity and high-level deuterium incorporation. This result was published online at Sci. Adv. (DOI: 10.1126/sciadv.aba0946) under the title “Bioinspired Design of a Robust d3-Methylating Agent (DMTT)”.
Methylation is generally considered to be one of the most practical strategies for discovering new drugs in pharmaceutical chemistry. The incorporation of methyl group can effectively change the molecular recognition of endogenous and exogenous molecules by bioreceptors, alter the target selectivity and metabolic pathways in vivo (Chem. Rev. 2011, 111, 5215; Angew. Chem. Int. Ed. 2013, 52, 12256.). The deuteration can also significantly impart dramatic improvements of biological process (ACS Med. Chem. Lett. 2013, 4, 349; Bioorg. Med. Chem. Lett. 2015, 25, 167). Combined the above, d3-methyl group might play vital role in the metabolic pathways related to absorption, distribution, and metabolism in organisms: in 2017, Austedo with two d3-methyl group was approved by the FDA as the first deuterated drug. In addition, a series of drugs containing d3-methyl group are developed and used in clinical research. From the viewpoint of synthetic chemistry, the design of d3-methylating agent is the most ideal and effective approach because it has the capability to directly introduce the D-labeled methyl group into structurally diverse molecules.
S-adenosylmethionine (SAM) is widely used as methylating reagent in most biological methylation; while Umemoto reagent is a commercially available electrophilic trifluoromethylating agent. Bioinspired by the reactivity of SAM, together with the design principle of Umemoto’s reagent, we simplified the SAM structure and designed a novel d3-methylating agent DMTT (Figure 1). DMTT could be simply prepared from available substrates on a large scale, and the compound is very stable when stored as a solid at room temperature. Furthermore, dibenzothiophene was generated as byproduct after the d3-methylation, which can further used to synthesis DMTT to achieve the goal of the atomic economy.
Figure 1. Bioinspired invention of DMTT
A study of its application revealed that the d3-methylation of DMTT with substrates proceeds in a biomimetic process, thus exhibiting excellent chemoselectivity under extremely mild conditions analogy to SAM chemistry in living organism (Figure 2). A series of d3-methylated organic molecules and deuterated pharmaceuticals containing various nucleophiles, such as carboxylic acid, phenol, thiol, amine, and so on, were synthesized under the mild system with excellent selectivity. Compared with traditional d3-methylating reagents, DMTT exhibits much higher selectivity, especially in the modification of natural products and pharmaceutical molecules. Furthermore, we have developed its application in the transition metal-catalyzed C‒H bond activation and the base-mediated d2-methyleneation of olefins.
Figure 2. Application in selective d3-methylation
The first author is associate professor Wang Minyan. This work was supported by the National Natural Science Foundation of China (21972064, 21901111), the Natural Science Foundation of Jiangsu Province (BK20170632), and the State Key Laboratory of Coordination Chemistry.
Full text link: https://advances.sciencemag.org/content/6/19/eaba0946.full
Related patents: Preparation method of diaryl thiothiophene or diaryl sulfide type deuterated alkyl, Chinese Patent, 201810770921.4